Many attempts have been made in the pharmaceutical art to provide a method by which therapeutically active medicaments can be directly tableted or mixed with a direct compression vehicle and thereafter directly tableted.
Very few therapeutically active medicaments can be directly tableted due to unacceptable flow characteristics and compressibility factors of the crystalline or powdered medicament, and also due to the small amounts of medicament needed to provide the desired effect. Therefore, it is a common practice to use an inert ingredient, i.e., excipients, diluents, fillers, binders and the like, such that the combination of the same with the medicament provides a material which can be directly compressed into tablets. In order to provide a directly compressible product, these excipients must have certain physical properties, including flowability, sufficient particle size distribution, binding ability, acceptable bulk and tap densities, and acceptable dissolution properties in order to release the medicament upon oral administration.
U.S. Pat. No. 3,639,169 (Broeg et al.) discloses one such direct compression vehicle for a therapeutically active medicament which consists of an insoluble or soluble diluent such as lactose dispersed in a matrix of a hydrophilic hydratable high polymer such as hydrophilic polysaccharides, hydrocolloids or proteinaceous materials. The polymer, diluent and water are mixed and the resulting dispersion is dried, forming a film. The cooled film is fragmented, ground to the desired particle size and then blended with a desired medicament.
In another method disclosed in U.S. Pat. No. 3,079,303 (Raff et al.), a granular excipient for making tablets is prepared by spray drying a slurry of 50%-98% filler, 1%-50% disintegrant, and 1%-50% binder. A medicament is then added to the excipient and the finished product is tableted.
It has become desirable to provide pharmaceutical formulations which utilize slow release profiles, an objective not contemplated in Broeg et al., Raff et al. or other similar prior art. The advantages of slow release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level over a longer period of time while increasing patient compliance by reducing the number of administrations necessary to achieve the same.
Slow release excipients have been developed which attain their goals by a wide variety of methods. For instance, U.S. Pat. No. 3,629,393 (Nakamoto) utilizes a three-component system to provide slow release tablets in which granules of an active ingredient with a hydrophobic salt of a fatty acid and a polymer are combined with granules of a hydrocolloid and a carrier and granules of a carrier and an active or a buffering agent and then directly compressed into tablets. U.S. Pat. No. 3,728,445 (Bardani) discloses slow release tablets formed by mixing an active ingredient with a solid sugar excipient, granulating the same by moistening with a cellulose acetate phthalate solution, evaporating the solvent, recovering the granules and compressing under high pressure. These disclosures concentrate their attention to the type and combination of polymers and/or gums used, and processes for mixing the same, and therefore have not provided a directly compressible form of gums/polymers and adjuvants which can be used for a wide range of medicaments.
Other slow release excipients are disclosed in the prior art which are directed to particular therapeutically active medicaments.
In one such disclosure, U.S. Pat. No, 3,456,049 (Hotko et al.), a slow release benzothiadiazine diuretic tablets are prepared by mixing a fatty substance such as hydrogenated vegetable oil, alginic acid, a granulating liquid, a potassium salt and the benzothiadiazine. The wet mass is screened, dried, and then compressed into tablets. Similarly, U.S. Pat. No. 4,692,337 (Ukigaya et al.) provides a slow release excipient for theophylline which utilizes 5-200 parts of ethyl cellulose for each 100 parts theophylline, and optionally contains a filler such as lactose or a lubricant. The ingredients are mixed and compression molded into tablets. In yet another example, U.S. Pat. No. 4,308,251 (Dunn et al.), a sustained release aspirin formulation in which 0.8-1.6 percent of a release controlling agent (cellulose acetate phthalate) and 1.0-7.5 percent of an erosion-promoting agent (corn starch) by weight per tablet. A wet granular mass is formed, dried, reduced in particle size and compressed into tablets.
More recently, a great deal of attention in the pharmaceutical field has turned to the use of various hydrocolloid materials such as hydroxypropylmethyl cellulose in providing a slow release matrix for a variety of medicaments.
For example, U.S. Pat. No. 4,389.393 (Schor et al.) describes a slow release carrier base material of one or more hydroxypropylmethyl celluloses and up to 30% by weight of a mixture of methylcellulose, sodium carboxymethylcellulose and/or cellulose ether which can be mixed with a medicament and other needed ingredients such as binders, lubricants, etc. and then tableted. At least one of the hydroxypropylmethyl celluloses must have a methoxy content of 16%-24% by weight, a hydroxypropyl content of 4%-32% by weight, and a number average molecular weight of at least 50,000. The carrier base constitutes less than about one third of the weight of the solid unit dosage form.
It is acknowledged in Schor et al. that in order to make tablets using this carrier base, other ingredients which are conventional in tablet making must necessarily be included, such as binders, fillers, disintegrating agents and the like. Only the completed mixture, which includes these additional ingredients, possess sufficient properties to produce tablets having the necessary hardness and low level of friability. Thus, the carrier base of the Schor et al. disclosure is not directed to the tableting aspects.
U S. Pat. No. 4,704,285 (Alderman) discloses solid slow release tablets containing 5%-90% hydroxypropyl cellulose ether, 5%-75% of an optional additional hydrophilic colloid such as hydroxypropylmethyl cellulose, an effective amount of an active medicament, and optional binders, lubricants, glidants, fillers, etc. The hydroxypropyl cellulose ether is in the form of a finely sized powder and provides a longer release pattern than identical compositions having coarser particles. However, Alderman acknowledges the necessity of the additional excipients in order to form an acceptable solid tablet, (i.e. fillers, binders, lubricants and glidants). In preferred embodiments, these excipients comprise from 63.5%-94% of the tablet.
The carrier bases which provide the slow release profiles in these disclosures can only be compressed into a tablet or a solid dosage form with the aid of other conventional tableting adjuvants such as binders and the like, and therefore contribute only to the slow release aspect of the final solid unit dosage form and not to the tableting aspects. In other words, in each of these disclosures it is necessary for to first determine the physical properties of the active medicament to be tableted and thereafter proceed through a series of trial and error experiments in order to determine the optimal amount of gums/polymers and other adjuvants to produce the right formulation which is free flowing and which can be compressed to a slow release solid dosage unit. This procedure is time intensive and costly.
Similarly, slow release excipients disclosed to date which incorporate virtually any synthetic polymer such as hydroxypropylmethylcellulose, methyl cellulose, polyvinylpyrollidone, and any natural gum such as acacia tragacanth, alginates, chitosan, xanthan, pectin and others to date have been mainly directed to the slow release aspect and do not satisfactorily address the tableting aspect. This is because these materials are not available in the necessary physical form that is essential for forming a solid unit dosage form.
The failure of slow release excipients such of the above to be regarded as to their tableting properties is due, for instance, to their necessarily very fine particle size, which property does not lend itself well to flowability. Also, hydroxypropylmethyl cellulose polymers and the like are not particularly good binding agents, a problem which is amplified when other poorly binding excipients or medicaments are included in a formulation. Thus, at higher percentages of such polymers in the final mixture, it becomes difficult if not impossible to provide a good flowing tablet formulation for direct compression without the use of further excipients, and experimentation.
The tableting aspect has been addressed, albeit unsatisfactorily, in U.S. Pat. No. 4,590,062 (Jang). Jang discloses a dry direct compressed slow release tablet containing from 0.01 to 95 parts by weight of an active ingredient combined with a matrix blend of 1-96 parts of a hydrophobic carbohydrate polymer and 4-99 parts of a wax, and a fatty acid material or neutral lipid. The tablets can be made by dry blending the active ingredient with the matrix blend and compressing. However, while this combination of ingredients can provide a directly compressible tablet, the formulator is still required to perform a great deal of experimentation to provide the correct release profile for the chosen medicament, given the wide range of wax (used for its binding and compacting properties) which can be included.
It is therefore an object of the present invention to provide a free-flowing directly compressible slow release excipient which can be used for a wide variety of therapeutically active medicaments.
It is another object of the present invention to provide an excipient which can be prepared by wet granulation to form controlled release tablets.
It is a further object of the present invention to provide an excipient having the properties set forth above which can be used with both relatively soluble and relatively insoluble therapeutically active medicaments.
It is a further object of the present invention to provide a free-flowing directly compressible slow release excipient which is relatively inexpensive to manufacture due to the lack of coatings and expensive equipment.